Dabrafenib-Panobinostat Salt: Improving the Dissolution Rate and Inhibition of BRAF Melanoma Cells.

Abstract

Cocrystallization of the drug-drug salt-cocrystal of the histone deacetylase inhibitor (HDACi) panobinostat (PAN) and b-rapidly accelerated fibrosarcoma (BRAF) inhibitor dabrafenib (DBF) afforded single crystals of a two-drug salt stabilized by N+-H···O and N+-H···N- hydrogen bonds between the ionized panobinostat ammonium donor and dabrafenib sulfonamide anion acceptor in a 12-member ring motif. A faster dissolution rate for both drugs was achieved through the salt combination compared to the individual drugs in an aqueous acidic medium. The dissolution rate exhibited a peak concentration (Cmax) of approximately 310 mg cm-2 min-1 for PAN and 240 mg cm-2 min-1 for DBF at a Tmax of less than 20 min under gastric pH 1.2 (0.1 N HCl) compared to the pure drug dissolution values of 10 and 80 mg cm-2 min-1, respectively. The novel and fast-dissolving salt DBF-·PAN+ was analyzed in BRAFV600E melanoma cells Sk-Mel28. DBF-·PAN+ reduced the dose-response from micromolar to nanomolar concentrations and lowered IC50 (21.9 ± 7.2 nM) by half compared to PAN alone (45.3 ± 12.0 nM). The enhanced dissolution and lower survival rate of melanoma cells show the potential of novel DBF-·PAN+ salt in clinical evaluation.